Automated system for continuously and automatically calibrating electrochemical sensors

ABSTRACT

An electrochemical sensor system that continuously monitors and calibrates the sensors included in the system. The invention also includes a method for determining failure patterns of a sensor and incorporating into an electrochemical sensor system the ability to recognize the failure pattern and initiate remedial action.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.10/227,618, filed on Aug. 22, 2002, which claims priority to U.S.provisional patent application Ser. No. 60/314,267, filed Aug. 22, 2001,the entire disclosures of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention is related to the field of electrochemicalsensors, particularly to the increased accuracy of electrochemicalsensors used to measure analytes in body fluids.

BACKGROUND OF THE INVENTION

In a variety of clinical situations, it is important to measure certainchemical characteristics of the patient's blood, such as pH, hematocrit,the ion concentration of calcium, potassium, chloride, sodium, glucose,lactate, creatinine, creatine, urea, the partial pressure of O₂, and/orCO₂, and the like. These situations range from a routine visit of apatient to a physician's office to the monitoring of a patient duringopen-heart surgery. Further, the required speed, accuracy, and otherperformance characteristics of such measurements vary with eachsituation.

Electrochemical sensor systems such as those described in U.S. Ser. No.09/549,968, U.S. Ser. No. 09/872,247, U.S. Ser. No. 09/871,885, and U.S.Ser. No. 09/872,240, the entire disclosure of each incorporated byreference herein, are typically used to provide this blood-chemistryanalysis on a patient's blood. Conventional sensor systems are eitherstand-alone machines or machines that connect to an extracorporealshunt. Alternatively, these sensors can also connect to an ex vivo bloodsource, such as a heart/lung machine. To obtain a blood sample from aheart/lung machine, for example, small test samples of blood can bediverted off-line from either the venous or arterial flow lines of theheart/lung machine to a bank of micro-electrodes of the electrochemicalsensor system.

Conventional micro-electrodes generate electrical signals proportionalto chemical characteristics of the blood sample. To generate theseelectrical signals, the sensor systems may combine a chemical orbiochemical recognition component (e.g., an enzyme) with a physicaltransducer such as a platinum electrode. Traditional chemical orbiochemical recognition components selectively interact with an analyteof interest to generate, directly or indirectly, the needed electricalsignal through the transducer.

The selectivity of certain biochemical recognition components makes itpossible for electrochemical sensors to accurately detect certainbiological analytes, even in a complex analyte mixture such as blood.Despite the high degree of selectivity of these sensors, the accuracy ofsuch sensors depends on keeping the sensors calibrated at all times. Onetechnique used to monitor sensor calibration is to manually verify thecalibration of the sensor using an external verification solution. Thistechnique, however, is often labor-intensive, as it is typicallyperformed several times a day. Further, the delay between the manualverifications of the sensor may prevent a timely discovery of anuncalibrated sensor.

Another method used to monitor sensor calibration is to monitor thesensor with an external verification solution automatically at set timeintervals, such as every 8 hours. Although not as labor-intensive asmanually verifying a sensor, this technique may instead make itdifficult to detect errors in a timely fashion, thereby enablinginaccurate readings from the sensor if it becomes uncalibrated beforethe scheduled verification (and correction) time. Further, automaticmonitoring methods may not detect a small fraction of uncalibratedsensors. This gap in sensitivity of the automatic monitoring methods mayresult in uncalibrated sensors not receiving the needed correctiveactions.

SUMMARY OF THE INVENTION

One objective of the present invention is to provide a system and methodfor the automatic and continuous monitoring of an electrochemical sensorsystem. The system of the present invention maintains the calibration ofall electrochemical sensors in the electrochemical sensor systemautomatically at all times without the scheduled involvement of anoperator. The system of the present invention further recognizes and iscapable of correcting failures in the calibration of a sensor that aretypically not recognized by standard monitoring methods.

In one aspect of the present invention, a method for automaticmonitoring of an electrochemical sensor system includes providing anelectrochemical sensor system including at least one electrochemicalsensor. The method includes analyzing an analyte that includes a knownconcentration in a first reference solution to determine a firstmeasurement of the known concentration of the analyte. The method alsoincludes analyzing the analyte in the first reference solution todetermine a second measurement of the known concentration of theanalyte. The method additionally includes comparing the knownconcentration, first measurement of the known concentration and secondmeasurement of the known concentration of the analyte. In yet anotherstep, the method includes automatically initiating corrective action ifthe first measurement of the analyte is substantially similar to thesecond measurement of the analyte and the first and second measurementsare substantially dissimilar to the known concentration of the analyte.

In one embodiment, the corrective action includes calibrating theelectrochemical sensor according to the known concentration of theanalyte of the reference solution. The corrective action may alsoinclude rinsing the electrochemical sensor. In yet another embodiment,the electrochemical sensor system includes a sample flow channeldisposed adjacent to the electrochemical sensor.

In another aspect of the invention, a method for automatic monitoring ofan electrochemical sensor system for measuring an analyte in a fluidsample includes providing an electrochemical sensor system including atleast one electrochemical sensor. The method also includes analyzing ananalyte including a known concentration in a first reference solution todetermine a first measurement of the known concentration of the analyte,and analyzing the analyte in the first reference solution to determine asecond measurement of the known concentration of the analyte. The methodadditionally compares the known concentration, first measurement of theknown concentration and second measurement of the known concentration.The method also measures the analyte concentration in the fluid sampleif the first measurement of the known concentration of the analyte inthe first reference solution and the second measurement of the knownconcentration of the analyte in the first reference solution aresufficiently dissimilar and the second measurement of the knownconcentration of the first reference solution is sufficiently similar tothe known concentration of the reference solution.

In another aspect of the invention, an electrochemical sensor systemincludes a first reference solution having a known concentration of atleast one analyte. The system also includes an electrochemical sensorwhich analyzes the analyte to determine a first measurement and a secondmeasurement of the known concentration of the analyte. The system alsohas a comparator to compare the known concentration, the firstmeasurement of the known concentration, and the second measurement ofthe known concentration of the analyte. The system additional has acorrective action device which initiates corrective action if the firstmeasurement of the analyte in the first reference solution issubstantially similar to the second measurement of the analyte in thefirst reference solution and the first and second measurements aresubstantially dissimilar to the known concentration of the analyte. Inone embodiment, a cartridge holds the first reference solution.

These and other objects, along with advantages and features of thepresent invention herein disclosed, will become apparent throughreference to the following description, the accompanying drawings, andthe claims. Furthermore, it is to be understood that the features of thevarious embodiments described herein are not mutually exclusive and canexist in various combinations and permutations.

BRIEF DESCRIPTION OF THE DRAWING

The foregoing and other objects, features and advantages of the presentinvention disclosed herein, as well as the invention itself, will bemore fully understood from the following description of preferredembodiments and claims, when read together with the accompanyingdrawings. The drawings are not necessarily to scale, emphasis insteadgenerally being placed upon illustrating the principles of theinvention.

FIG. 1 is a schematic diagram of the components of an electrochemicalsensor apparatus including a sensor cartridge with a bank of sensors anda thermal block for accelerated hydration and calibration of thesensors.

FIG. 2 illustrates a reverse frontal view of the sensor card, partlyfragmentary, of a cartridge embodiment of the invention.

FIGS. 3A-3C illustrate a method of the electrochemical sensor systemoperation.

FIGS. 4A-4B illustrate failure patterns and corrective actions relatedto internal reference solution B.

FIG. 5 illustrates an embodiment of a corrective action report.

FIG. 6 illustrates an embodiment of a delta chart.

DETAILED DESCRIPTION OF THE INVENTION

The present invention pertains to electrodes and electrochemical sensorsystems for measuring analyte levels of aqueous samples including, butnot limited to, blood serum or other body fluids. In one aspect, theinvention is directed to reducing operator interaction for calibrationof the system. The invention is further directed to a system for thecontinuous monitoring and continuous calibration of the sensors in thesystem. The present invention is also related to a method fordetermining failure patterns of a sensor and for recognizing the failurepattern and initiating remedial action to correct the error in thesensor indicated by the failure pattern.

Definitions

In order to more clearly and concisely point out and describe thesubject matter which applicant regards as the invention, the followingdefinitions are provided for certain terms used in the followingdescription and claims.

As used herein, the term “electrode” refers to a component of anelectrochemical device which makes the interface between the externalelectrical conductor and the internal ionic medium. The internal ionicmedium, typically, is an aqueous solution with dissolved salts. Themedium may also comprise proteins in a stabilizing matrix.

Electrodes are one of three types: working or indicator electrodes,reference electrodes, or counter electrodes. A working or indicatorelectrode measures a specific chemical species, such as an ion. Whenelectrical potentials are measured by a working electrode, the method istermed potentiometry. All ion-selective electrodes operate bypotentiometry. When current is measured by a working electrode, themethod is termed amperometry. Oxygen measurement is carried out byamperometry. Working electrodes may also have an enzyme in an enzymelayer. The enzyme layer is part of a composite layer that is in closecontact with the electrode. The enzyme, which is specific to aparticular analyte, produces hydrogen peroxide, a by-product of thecatalytic reaction of the enzyme on the analyte. Hydrogen peroxide isdetected by the electrode and converted to an electrical signal. Areference electrode serves as an electrical reference point in anelectrochemical device against which electrical potentials are measuredand controlled. In one embodiment, silver-silver nitrate forms thereference electrodes. Other types of reference electrodes aremercury-mercurous chloride-potassium chloride or silver-silverchloride-potassium chloride. A counter electrode acts as a sink for thecurrent path.

As used herein, the term “sensor” is a device that responds tovariations in the concentration of a given chemical species, such asglucose or oxygen, in a sample, such as a body fluid sample. Anelectrochemical sensor is a sensor that operates based on anelectrochemical principle and requires at least two electrodes. Forion-selective measurements, the two electrodes include an ion-selectiveelectrode and a reference electrode. Amperometric enzyme electrodesadditionally require a third electrode, a counter electrode. Moreover,enzyme sensors based on two electrodes (e.g., a working and referenceelectrode) are also common.

As used herein, the term “calibration” refers to the process by whichthe response characteristics of a sensor to a specific analyte aredetermined quantitatively. To calibrate a sensor, the sensor is exposedto at least two internal reference solutions, or process controlsolutions, each solution having a different, known concentration of theanalyte. The responses, i.e., signals, measured by the sensor relativeto the concentrations of the analyte in the two different internalreference solutions serve as reference points for measurements of thesame analyte in samples having unknown concentrations of the analyte.

As used herein, the term “drift” refers to a measure of the differencebetween the value of a first reading by a sensor of a sample and asecond reading by the same sensor analyzing the same sample.

As used herein, the term “verification procedures” refers to one or moretechniques used to verify that one or more sensors are properlycalibrated.

As used herein, the term “failure patterns” refers to any indicatorgiven by the sensor to indicate that it is not calibrated correctly. Forinstance, a failure pattern may include a drift error in a certaindirection.

One-point and two-point drift calculations for pH, pCO₂, Na, K and Camay be calculated by the following algorithms described below.

Measured values for Na, K and Ca for two-point cal:(A−B)/S′[Cm] _(A) =[C] _(B)*10 mmol/L  (1)(B−B)/S′[Cm] _(B) =[C] _(B)*10 mmol/L  (2)

Measured values for Na, K and Ca for one-point cal:(B₂−B′)/S[Cm] _(B) =[C] _(B)*10 mmol/L  (3)

Measured values for pCO₂ for two-point cal:(B−A)/S′pCO₂MA=PCO₂ B*10 mmHg  (4)(B′−B)/S′pCO₂ MB=pCO₂ B*10 mmHg  (5)

Measured values for PCO2 for one-point cal:(B−B₂)/SpCO₂ MB=pCO₂ B*10 mmHg  (6)

Measured values for pH for two-point cal:pHMA=(B−A)/S′+pHB pH unit  (7)pHMB=(B′−B)/S′+pHB pH unit  (8)

Measured values for pH for one-point cal:pHMB=(B′−B2)/S+pHB pH unit  (9)

In the algorithms above, the [Cm]_(A) and [Cm]_(B), pCO₂MA and pCO₂ MB,or pHMA and pHMB are the measured A and B values. A and B before A arethe two-point calibration. B′ is the one-point calibration before the Bor B₂. B₂ is the latest one-point calibration. S is the slope from thelatest two-point calibration, and S′ is the slope from the previoustwo-point calibration. [C]_(B), pCO₂B and pHB are the “B” bar-codevalues. The drift is the difference between the measured and thebar-code value. In the drift calculations for two-point calibration, theS′ is used as long as it can be calculated. If S′ cannot be calculated,the S (current slope) is used in place of the S′. If there is a sampleor “A” calibration between the “B” and “B′” or between the “B₂” and“B′”, then the following equations are used for the measured “B”:(B₂−B′)/(K*S)[Cm] _(B) =[C] _(B)*10 mmol/L  (10)(B′−B2)/(K*S)pCO₂ MB=pCO₂ B*10 mmHg  (11)pHMB=(B′−B ₂)/(K*S)+pHB pH unit  (12)

If there is a “C” calibration or “rinse” between the “B” and “B′” orbetween the “B₂” and “B′”, then the following equations are used for themeasured “B”:(B₂−B′)/(K*S)[Cm] _(B) =[C] _(B)*10 mmol/L  (13)(B′−B₂)/(K*S)pCO₂ MB=pCO₂ B*10 mmHg  (14)pHMB=(B′−B ₂)/(K*S)+pHB pH unit  (15)

In the equations above, K is a constant value representing a sensitivityfactor. In one embodiment, a lower K value represents a less sensitivesensor system 8 with respect to the measurement of an A concentrationand an even less sensitive sensor system 8 with respect to themeasurement of a C concentration. In one embodiment, the range of valuesfor K is approximately 1-3, where 1 represents the most sensitive and 3represents the least sensitive. In some embodiments, the K value for anA concentration is preferably 1.5 and within the range of 1-2. Inadditional embodiments, the K value for a C concentration is within therange of 2-4. Moreover, in some embodiments, the K value represents abaseline and substantially equals 1 for B concentrations. Althoughdescribed above as preferable ranges and values, the value of K can takeon any value to represent the sensitivity factor associated with aparticular concentration.

If there is a one-point drift failure, or error, for pH, PCO2, Na, K orCa, and if the repeated calibration fails for drift, then, beforereporting the drift failure, another drift check may be performed. Inthis alternate drift check, the B′ in equations 3, 6, or 9 is replacedwith the B mV prior to the drift failure. If this alternate drift checkpasses, then the repeated calibration should pass and should bereported. If this alternate drift check fails, then the initial repeatedcalibration (the retried calibration that failed) should be reported. Inone embodiment, this process only applies to the first retry after a Bdrift error.

One-point and two-point drift Calculations for pO₂.

Oxygen Drift:pO₂ MA=(pO₂ B−pO2C)*(A−C)/(B ₂ −C)+pO₂C mmHg  (1)pO₂ drift A=pO₂ MA−pO₂ MA′ mmHgpO₂ MB=(pO₂ B−pO2C)*(B ₂ −C)/(B′−C)+pO₂C mmHg  (2)pO₂ drift B=pO₂ MB−pO₂B mmHgpO₂ MC=(pO₂B−pO₂C)*(C−C′)/(B ₂ −C′)+pO₂C mmHg  (3)pO₂ drift C=pO₂ MC−pO₂C mmHg

pO₂MA, pOMB and pO₂MC are the measured oxygen in the Cal A, Cal B andCal C respectively. pO₂MA′ is the measured oxygen value from theprevious Cal A (the very first value will be determined in warm-up).pO₂B and pO₂C are the oxygen values in the B bag and C bag,respectively. A is the oxygen mV value from the current Cal A. C is theoxygen mV value from the most recent Cal C. C′ is the oxygen mV valuefrom the previous Cal C. B′ is the oxygen mV value from the Cal B beforethe B2. B2 is the oxygen mV value from the current Cal B.

Several exceptions for the oxygen drift calculations exist. If there isa sample or “A” calibration between the “B2” and “B′”, then equation 2is modified to:pO₂ MB=(pO₂B−pO₂C)*((B ₂ −B′)/(K*(B′−C))+1)+pO₂C  (4)If there is a “C” calibration or “Rinse” between the “B₂” and “B′”, thenequation 2 is modified to:pO₂ MB=(pO₂B−pO₂C)*((B ₂ −B′)/(K*(B′−C))+1)+pO₂C  (5)

If there is a “B” drift failure for pO₂ and if the repeated calibrationfails, then, before reporting the drift failure, another drift check maybe performed. In this alternate drift check, the B′ in equations 2 isreplaced with the B mV prior to the drift failure. If this alternatedrift check passes, then the repeated calibration should pass and bereported. If this alternate drift check fails, then the initial repeatedcalibration (the retried calibration that failed) should be reported.This process applies only to the first retry after a B drift failure.

Electrochemical Sensor System

Referring to FIG. 1, the electrochemical sensor system 8 employs asensor assembly, generally indicated at 10, incorporating a plurality ofelectrodes adapted to make electrical measurements on a sample, such asa blood sample, introduced to the sensor assembly 10. Blood samples tobe analyzed by the system 8 are introduced through a sample inlet 13 a.Blood samples are obtained by, for example, phlebotomy or are derived ona periodic basis from an extracorporeal blood flow circuit connected toa patient during, for example, open heart surgery. Blood samples may beintroduced into the sample inlet 13 a through other automatic means, ormanually, such as by syringe. The blood samples may be introduced asdiscrete samples.

The electrochemical system 8 can also contain a disposable cartridge 37.A cartridge of a similar type is set forth in detail in U.S. Pat. No.4,734,184, U.S. Ser. No. 09/871,885, U.S. Ser. No. 09/872,240, and U.S.Ser. No. 09/872,247 the entirety of the specifications incorporated byreference herein. In one embodiment of the invention, the cartridge 37also includes a rotor-for-sample inlet arm 5.

Referring to FIG. 1, in one embodiment of the invention, theelectrochemical sensor system 8 incorporates in the cartridge 37 atleast three prepackaged containers 14, 16, and 17, each containing aninternal reference solution having known values of the parameters to bemeasured by the system 8. For purposes of reference, the solutioncontained within the prepackaged container 14 will be termed internalreference solution A, the solution contained within the prepackagedcontainer 16 will be termed internal reference solution B, and thesolution contained within the prepackaged container 17 will be termedinternal reference solution C. Any prepackaged container 14, 16, and 17however, can contain any internal reference solution (e.g., internalreference solution C). Each of the prepackaged containers 14, 16 and 17contain a sufficient quantity of its internal reference solution toallow the system 8 to be calibrated a substantial number of times beforethe prepackaged container 14, 16, 17 becomes empty. In one embodiment,the system 8 is calibrated 1500 times for ‘B’, 150 times for ‘A’, and 20times for ‘C’. When one or more of the containers 14, 16 and 17containing the internal reference solutions are empty, the cartridgecontaining prepackaged containers 14, 16 and 17 is replaced.

With continued reference to FIG. 1, in one embodiment, the prepackagedcontainer 14 is connected to the input of a multi-position valve 18through a flow line 20, and the prepackaged container 16 is connected toa second input of the multi-position valve 18 through a flow line 22. Inyet another embodiment, the container 17 is connected to a third inputof the multi-position valve 18 through a flow line 21. The output line12 is the output of the multi-position valve 18 and is connected to thesample input line 13 through a stylus 11. Depending upon the position ofthe valve 18, the input lines 20, 21, 22 or air, is open to the valve18. Similarly, when the stylus is in a normal position (position 11 b)of the sample input line 13 b, line 12 b is open to the sample inputline 13 b and allows passage of the internal reference solution, orrinse solution, or air through the sample input line 13 b to the sensorassembly 10 through line 24, facilitated by the operation of aperistaltic pump schematically illustrated at 26. In a sample acceptingmode (13 a) in which the input line is in position 13 a, however, a line12 a is separated from the sample input line (position 13 b) and thesample is introduced directly to the sensor assembly 10 through line 24,facilitated by the operation of the peristaltic pump 26.

Referring to FIG. 1, the cartridge 37 also includes a container 28 for asolution surrounding a reference electrode. The container 28 isconnected to the sensor assembly 10 by a flow line 30. The systemfurther includes a waste container 32, which receives the blood samples,the internal reference solution and the solution for the referenceelectrode 28 after they have passed through the sensor assembly 10. Inone embodiment, the sensor assembly 10 transmits these samples (e.g.,blood samples) to the waste container 32 via a flexible conduit 34.

Both the waste flow conduit 34 and the flow line 30 for the solution forthe reference electrode includes sections of flexible walled tubing thatpass through the peristaltic pump 26. The pump 26 compresses and strokesthe flexible sections of the flow lines 30 and 34 to induce a pressuredflow of solution for the reference electrode from its container 28 tothe electrode assembly 10. This compression and stroking also creates anegative pressure on the waste products in flow line 34 so as to drawfluids in the flow line 24 through passages in the electrode assembly 10past the membranes of the sensors. This arrangement, as opposed to thealternative of inducing positive pressure on the blood and calibratingsolutions to force them through the electrode assembly 10, avoids theimposition of unnecessary and possibly traumatic mechanical forces onthe blood sample, thereby minimizing the possibility of a leak in theelectrode assembly 10.

Cartridge 37 also contains a sensor card 50, illustrated for example inFIG. 2, which provides a low volume, gas tight chamber in which thesample, such as a blood sample, internal reference solution, or amonomer-containing solution, is presented to one or more electrochemicalsensors, i.e., the pH, pCO₂, pO₂, Na⁺, Ca⁺⁺, glucose, lactate, creatine,creatinine and hematocrit sensors. The sample and the referenceelectrode solution (from container 28) are integral parts of the chamberand are collectively indicated as the electrode assembly 10. Chemicallysensitive, hydrophobic membranes typically formed from polymers, such aspolyvinyl chloride, specific ionophores, and a suitable plasticizer, canbe permanently bonded to the chamber body. These chemically sensitive,hydrophobic membranes are the interface between the sample orcalibrating solutions and the buffer solution in contact with the inner(silver/silver chloride) electrode.

Blood samples that have been analyzed are prevented from flowing backinto the sensor card 50 from the waste container 32 due to the presenceof a one-way check 33 valve 33 in the waste line 34. After use in thesystem 8, the cartridge 37 is intended to be discarded and replaced byanother cartridge.

Sensors may be available as a bank of electrodes 10 fabricated in aplastic card 50 and housed in the disposable cartridge 37 thatinterfaces with a thermal block assembly 39 of a suitably adaptedblood-chemistry analysis machine. The thermal block assembly 39 housesthe heating/cooling devices such as a resistive element or aPeltier-effect device, a thermistor 41 to monitor and control thetemperature, the electrical interface 38 between the sensors in theplastic card 50 and a microprocessor 40 through an analog board 45. Theanalog board 45 houses analog-to-digital and digital-to-analogconverters. The analog-to-digital converter receives the signal from theelectrode interface 38 and converts it into a digital form for theprocessor 40 to store and display. The digital-to-analog converter alsoreceives the digital signals from the processor 40 (e.g., thepolarization voltage for oxygen sensor) and converts them into an analogform and subsequently transmits them to the sensors for control.

Referring still to FIG. 1, the electrochemical sensor system 8 is formedupon insertion of the cartridge 37 into the electrochemical sensorapparatus. Upon insertion, the sensor assembly 10 fits into the heaterblock assembly 39, described in detail below, and the heating/coolingassembly regulated by the microprocessor 40 cycles the temperature ofthe sensor electrode card 50 and the solution in contact with thesensors inside the electrode card 50 through a specific temperature fora specified duration. The heater block assembly 39 is capable of rapidheating and cooling by, for example, a thermoelectric device applyingthe Peltier-effect. In one embodiment, the heater block assembly 39 ismonitored by thermistor 41 and both are controlled by the microprocessor40.

The electrode assembly 10 may also have a number of edge connectors 36in a bank which allow it to be plugged into a female matching connectorof the electrical interface 38 so that the electrodes formed on theassembly 10 may be connected to microprocessor 40 through the analogboard 45. The microprocessor 40 is connected to the multiport valve 18via a valve driver 43 by a line 42 and to the motor of the peristalticpump 26 via a pump driver 45 by a line 44. The microprocessor 40controls the position of the sample arm 5 through arm driver 15. Themicroprocessor 40 also controls the position of the valve 18 and theenergization of the pump 26 to cause sequences of blood samples,internal reference solutions, and external verification solutions to bepassed through the electrode assembly 10. When the internal referencesolutions from, for example, containers 14, 16 and 17 are pumped intothe electrode assembly 10, the electrodes forming part of the assemblymake measurements of the parameters of the sample and the microprocessor40 stores these values. Based upon measurements made during the passageof the internal reference solutions through the electrode assembly 10,and the known values of the measured parameters contained within theinternal reference solutions from containers 14, 16, and 17, themicroprocessor 40 effectively creates a calibration curve for each ofthe measured parameters. Thus, when a blood sample is passed through theelectrode assembly 10, the measurements made by the electrodes can beused to derive accurate measurements of the parameters of interest.These parameters are stored and displayed by the microprocessor 40. Themicroprocessor 40 is suitably programmed to perform measurement,calculation, storage, and control functions such as differences inelectrical potential across one or more electrodes.

Illustrated in FIG. 1, in one embodiment, the microprocessor 40 alsoincludes a comparator 47 to compare the measurements of concentration ofthe analyte being analyzed, as described in more detail below. As shown,the comparator may be part of the microprocessor 40. The comparator canbe, for example, any digital or analog circuit, such as an AND gate.

Additionally, the corrective action performed by the electrochemicalsensor system 8, as described in more detail below with respect to FIGS.4A-4B, are performed by a corrective action device. The correctiveaction device may be a component of the microprocessor 40. Thecorrective action device may also be a module or software programexecuted by the microprocessor 40. Although shown as an internalcomponent of the microprocessor 40, the corrective action device 49and/or the comparator 47 can alternatively be devices externally locatedfrom the microprocessor 40.

Internal Reference Solutions

In one embodiment of the invention, a composition of internal referencesolution A used for second point calibration is prepared at, forexample, 37° C. and at atmospheric pressure tonometered with 9% CO₂, 14%O₂, and 77% Helium gas, and has the following characteristics: pH 6.9organic buffer; pCO₂=63 mmHg; pO₂=100 mmHg; Na⁺=100 mmol/L; K⁺=7 mmol/L;Ca⁺⁺=2.5 mmol/L; glucose=150 mg/dL; lactate=4 mmol/L; creatine=0.5mmol/L; creatinine=0.5 mmol/L; surfactant and inert preservative.

In further embodiments of the invention, a composition of internalreference solution B used for one-point calibration and rinse isprepared at, for example, 37° C. and at 700 mmHg absolute pressuretonometered with 27% O₂, 5% CO₂, and 68% Helium gas; and has thefollowing characteristics: pH 7.40 organic buffer; pCO₂=34 mmHg; pO₂=180mmHg; Na⁺=140 mmol/L; K⁺=3.5 mmol/L; Ca⁺⁺=1.0 mmol/L; 20 mM cholinechloride; surfactant and inert preservative.

In yet other embodiments of the invention, a composition of internalreference solution C used for third-point calibration (for pCO₂ and pH),cleaning, low level oxygen calibration and in situ regeneration of theinner polymeric membrane for the enzyme sensors has the followingcharacteristics: NaOH=12 mM, NaHCO₃=86 mM, Na₂SO₃=20 mM, total Na⁺=140mM; KCL=6 mM; 15 mmol/L of m-phenylenediamine; 50 mM3-[(1,1-Dimethyl-2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid(AMPSO); 4.5 g/L polyoxyethylene (100) stearyl ether (Brij 700); 4.5 g/LPolyoxyethylene (35) castor oil (Cremophor EL); 3 g/L Polyoxyethylenefatty glyceride (Arlatone G); and 3 g/L block copolymer of ethyleneoxide and propylene oxide (Tetronic 90 R4). Additionally, the solutionfor the reference electrode (stored in container 28) may contain AgNO₃=1mmol/L; KNO₃=1 mol/L; and surfactant.

The compositions of the internal reference solutions A and B are chosenso that, for each of the characteristics measured by the system, a pairof values are obtained that are spaced over the range of permissiblevalues, thereby providing a balanced 2-point calibration for theinstrument. The internal reference solution C is chosen for low leveloxygen calibration and regeneration of the inner polymeric membrane inthe glucose, creatine, creatinine and lactate sensors.

In one embodiment, the A and B internal reference solution compositionsare prepared by premixing all of the constituents in a certain order,such as by starting with the buffer and ending with the sodiumbicarbonate salt, and then tonometering the solution with oxygen and CO₂mixed with helium to produce the desired level of pCO₂ and pO₂.

In one embodiment, the C internal reference solution is prepared with aslightly different procedure. Specifically, the salts, with theexception of sodium sulfite, m-phenylenediamine and sodium bicarbonate,are added to water and the solution is tonometered with helium to bringthe pO₂ to less than 30 mmHg. The remaining salts are then added to thesolution, and the final mixture is tonometered with mixture of pCO₂ andhelium to produce the desired pCO₂ level.

In one embodiment, at least one electropolymerizable monomer is added toat least one of the internal reference solutions, C in container 17, forexample. The absence of dissolved oxygen in the C internal referencesolution, due to the presence of sulfite ion, allows for a longer shelflife of electropolymerizable monomer in C because dissolved oxygen willoxidize the electropolymerizable monomer and thus render the monomerincapable of polymerizing. The electropolymerizable monomers (e.g.,m-phenylenediamine) may be included in an internal reference solution ata concentration in a range between about 1 to 100 mM, preferably 15 mM.The electropolymerizable monomer may also be included in the cartridge37 in a separate reservoir.

The temperature and pressure at which the internal reference solutionsare prepared and their method of packaging are such as to preclude thepossibility of dissolved gases going out of the solution in thecontainer 14, 16, 17. This can affect the concentration of gases in thecalibrating solutions and/or minimize the tendency for gases to permeatethrough materials.

The internal reference solutions are packaged with the solutionscompletely filling the containers, so that there is no headspace, byevacuating the containers prior to filling. By filling the internalreference solution into the evacuated flexible wall container 14, 16, 17at elevated temperatures and subatmospheric pressure, the solution willnot have any tendency at a lower use temperature to outgas and thusproduce gas bubbles in the container. Were outgassing to occur, theconcentrations of the gases in the solution would be affected, creatingan inaccuracy in the calibration of the instruments. Similarly, theinternal reference solutions are not packaged at too low of a pressure(e.g., not below about 625 mm of mercury) because the absorptivecapacity of the solution for gases conceivably increases as thepackaging pressure decreases. Moreover, below that pressure value, theabsorptive capacity of the solution may be sufficiently high so that thepressure value will tend to draw gases in through the slightly inherentpermeability of even the most gas-impervious flexible packaging materialover long periods of time. Accordingly, a packaging pressure in therange of 625-700 mm of mercury is preferred.

In one embodiment, an internal reference solution is prepared at atemperature in excess of its intended-use temperature so that, at thelower temperature, there is less tendency for outgassing of thedissolved gases. This solution may work in conjunction with the reducedpressure packaging to minimize the possibility of outgassing.

In one embodiment, internal reference solutions A and B are prepared ata temperature above their intended-use temperature at a controlledpressure close to atmospheric pressure. Through the use of an elevatedtemperature (e.g., 37° C.) the solution may be prepared at aboutatmospheric pressure without any possibility of subsequent microbubbleswithin the container or gas transfer through the container. This mayoccur, for instance, when the solutions are packaged in a zerohead-space, flexible gas-impervious container.

The envelopes used to create the prepackaged containers 14, 16, 17 areformed, for example, with rectangular sheets, heatsealed at the edgesand heatsealed at one corner to an inlet stem of the valve 18. The inletstem of the valve 18 can be used, for example, for filling purposes. Inone embodiment, the prepackaged containers 14, 16, and 17 and theprepackaged container lines 20, 22, and 21 are formed in a unitarycluster with the valve 18 so that gas-phase dead space in the lines 20,22, 21 is avoided. In a preferred embodiment for purging and filling theenvelope bags, the envelope is evacuated and then filled with theprepared solution. The bag is then shaken while the excess solutionflows out of the bag. This process removes any residual gas bubbles fromthe bag. The solution is then sealed in the container.

Solution for the Reference Electrode

The solution for the reference electrode disposed in prepackagedcontainer 28 is employed in the electrode assembly 10 as a supply sourceto a reference electrode. The reference electrode solution can provide aliquid junction and thereby isolate the reference electrode from thevarying electrochemical potential of the internal reference solution orthe blood in a manner which will be subsequently described. In apreferred embodiment, the solution is 1 mol/L potassium nitrate and 1mmol/L silver nitrate solution. The solution may also contain asurfactant such as Brij 35. The solution is packaged in a sealedflexible container with no headspace. The solution for the referenceelectrode is not an internal reference solution and does not functionsimilarly to the internal reference solutions A, B, and C.

Electrode Assembly

During operation of the pump 26, the electrode assembly 10 can receive aconstant, pulsating flow of the solution for the reference electrode vialine 30 and sequential, intermittent, pulsating flows of either theblood sample or one of the internal reference solutions via line 24. Theassembly may also provide a corresponding output of its waste productsto the waste collection bag 32.

Referring also to FIG. 2, by way of example, the electrode assembly 10in a preferred embodiment consists of a structurally rigid rectangularcard 50 of polyvinylchloride having a rectangular aluminum (or othersuitable material) cover plate 52 adhered to one of its surfaces. Thecover plate 52 closes off the flow channels 56 formed in one surface ofthe card 50. The cover plate 52 can also act as a heat transfer mediumfor hydrating the sensors by thermal cycling, described below. Moreover,the cover plate 52 can maintain the fluids flowing through the electrodeassembly 10, and the electrodes themselves, at a constant temperatureduring calibration and during measurement of relevant parameters in apatient sample. This may be achieved by measuring the temperature of theplate 52 and employing a suitable heating or cooling element, e.g., aPeltier-effect device and thermistor 41, to maintain the temperature ofthe plate 52 at a desired temperature.

A solution for the reference electrode is introduced to a well 64,formed in the surface of the substrate 50 in the same manner as theother flow channels 56 and similarly covered by the metal plate 52. Thesolution for the reference electrode flow line 30 passes through aninclined hole in the well 64. The well 64 is connected to the outputsection 34 of the flow channel 56 through a very thin capillary section66 formed in the surface of the plastic substrate 50 in the same manneras the main flow channels 56. The capillary channel 66 can besubstantially shallower and narrower than the main flow channel 56. Inone embodiment, the cross section of the capillary channel 66 isapproximately 0.5 sq. mm.

The pump 26 pumps solution for the reference electrode into the well 64via line 30 (see also FIG. 1). The solution fills the well, and is thenforced through the capillary section 66. The solution subsequently joinsthe output stream of fluid passing through the main flow channel section56 and then flows with it to the waste bag 32. The combined influence ofits higher density and the capillarity of the flow channel 66 serves tominimize any possibility of internal reference solution or blood passingdownward through the channel 66 to the well 64 and affecting theelectrochemical measurements.

As a blood sample or internal reference solution quantity introducedinto the flow channel 24 passes through the flow channel 56 to theoutput section 34, it passes over a number of electrodes as illustratedin FIG. 2. For example, the blood sample and/or internal referencesolution can be passed over a pO₂ sensor 70, an Na⁺ sensor 78, a Ca⁺⁺sensor 86, a K⁺ sensor 90, a glucose sensor 91, a lactate sensor 92, apCO₂ sensor 93, a pH sensor 94, hematocrit sensors 98, 100, a creatininesensor 116, and a creatine sensor 118.

Also referring to FIG. 1, the heat plate 52 abuts and forms one wall ofthe sample channel 56. The heat plate 52 is in contact with thePeltier-effect device of the thermal block assembly 39 described below.The thermal block assembly 39 is capable of changing and controlling thetemperature of the heat plate 52 between 15° C. and 75° C. Thetemperature change and control is monitored by a thermistor 41 andregulated by the microprocessor 40. An internal digital clock of themicroprocessor 40 may control time and may further cause themicroprocessor to apply power to the thermal block assembly 39 accordingto a preset program. Thus, the microprocessor 40 controls the thermalblock assembly 39, regulating the temperature setting and the durationof each set temperature of the heat plate 52.

Support

Referring again to FIG. 1, the electrodes of the present invention aresupported by the electrode, or support, card 50. The electrode card 50may be comprised of any material capable of bearing, either directly orby virtue of some intervening adhesion-improving layer, the othernecessary portions of the electrode which are described in detailhereinafter. Thus, the support may comprise materials such as ceramic,wood, glass, metal, paper or cast, extruded or molded plastic and/orpolymeric materials, etc. In one embodiment, the composition of thesupport carrying the overlying electrode components is inert. Thus, itdoes not interfere with the potentials observed, for example, by areaction with one of the overlying materials in an uncontrolled fashion.Moreover, the composition of the support withstands elevatedtemperatures to which the sensors can be exposed, such as during thetime required to hydrate and/or calibrate the sensors. In the case ofporous materials such as wood, paper or ceramics, the pores of thematerial may be sealed before applying the overlying electrodecomponents. The means of providing such a sealing are well known in theart.

According to a preferred embodiment of the present invention, thesupport comprises a sheet or film of an insulating polymeric material. Avariety of film-forming polymeric materials are well suited for thispurpose, such as, for example, cellulose acetate, poly(ethyleneterephthalate), polycarbonates, polystyrene, polyvinylchloride, etc. Thepolymeric support may be of any suitable thickness, typically from about20-200 mils. Similarly, thin layers or surfaces of other materialsmentioned above could be used. Methods for the formation of such layersare well known in the art.

Initial Operation of the Electrochemical Sensor System

When the cartridge with the sensor assembly 10 and the filled internalreference solution bags 14, 16 and 17 are first used, the valve 18 iscontrolled to direct one of the internal reference solutions, forexample internal reference solution B, into the sensor assembly so itentirely fills the flow channel. The pump is then stopped for apredetermined period of time (e.g., 10-30 minutes, preferably 12-15minutes) during which the dry chemical sensor electrodes are hydrated bythermal cycling (e.g., from 37° C. to 60° C. and back to 37° C.).

In one embodiment of the invention, the dry chemical electrode sensorassembly 10 is inserted into the electrochemical sensor system 8 and thevalve 18 is controlled by the microprocessor 40 to direct the internalreference solution B into the sensor assembly 10. Thermal block assembly39 is set at a temperature whereby the temperature of thermal plate 52is sufficient to heat the calibrating solution in contact with the drychemical sensor to a predetermined temperature (e.g., temperature in arange of 55° C. to 75° C., preferably 60° C.), for a predetermined time(e.g., 10-30 minutes, preferably 12 minutes). After the specified timeperiod, the microprocessor 40 reverses current flow through thethermoelectric device to cool thermal plate 52. The sensor card 50 andinternal reference solution in contact with thermal plate 52 are cooledto a cooling temperature (e.g., 37° C.). The temperature, controlled bythe microprocessor 40, is maintained at the cooling temperature (e.g.,37° C.) for the life of the cartridge 37.

After hydration of the sensors, the conditioning cycle of the enzymeelectrodes starts by pumping the C internal reference solution 17 to thesensor card 50 and soaking the electrodes for a predetermined soakingtime (e.g., 1 to 6 minutes, preferably for 3 minutes) while thepolarization potential of the enzyme electrodes is elevated from anormal voltage (e.g., 0.25 V) to an elevated voltage (e.g., 0.5 V)relative to the reference electrode. During the exposure to the Cinternal reference solution 17, the low oxygen level is calibrated. Uponcompletion of the C cycle, the rinse cycle starts by pumping rinsesolution from prepackaged container 17 to the flow channel 56 by theperistalic pump 26. During the rinse cycle, the polarization potentialof the enzyme electrodes is changed from 0.5 to 0.4 V in order toaccelerate the removal of the residues of the internal referencesolution C (from an inner interference rejection membrane). Followingthe completion of the rinse cycle, the polarization potential of theenzyme electrodes is lowered back to its normal level (e.g., about 0.25V) relative to the reference electrode.

The sensors are then calibrated with respect to internal referencesolutions A 14 and B 16. The cartridge 37 typically becomes ready forsample measurement within 30 minutes of cartridge 37 insertion into theelectrochemical sensor system 8.

Operation of the Assembly

Following the initial operation of the electrochemical sensor system 8and before the sensor system 8 is ready for use, the calibration of thesensors is verified. The verification step occurs once in the life ofthe sensor cartridge and uses external verification solutions to testthe calibration of the sensors. The verification procedure begins whenexternal verification solutions, including known concentrations of atleast one analyte, are introduced into the sensor channel and analyzedby the sensors in the cartridge. Two different external verificationsolutions having different concentrations of the analyte are analyzed toobtain two different analyte concentration points for each sensor.

Referring to FIG. 3A, the electrochemical sensor system 8 initiates asensor measurement (STEP 300) of the concentration of the externalverification solutions (EVS). It is then determined if the sensormeasurements are within the pre-set error limits with respect to theexternal verification solutions (STEP 301). The sensors are ready forsample measurement (STEP 302) if the concentration of the analyte inboth external verification solutions fall within an acceptable range ofa predetermined concentration of the analyte. An example of anacceptable range is within 5% of the known analyte concentration. If thesensors are ready for sample measurement (STEP 302), then theelectrochemical sensor system begins the automatic monitoring andcalibration of the sensors (STEP 304). During the automatic monitoringand calibration of the cartridge 37, the system automatically monitorsthe calibration of the sensors in the cartridge 37 using the internalreference solutions and initiates calibration of any sensor thatmeasures an analyte concentration outside of a preset acceptableconcentration range.

Following the initial verification of the calibration of the cartridge37 by external verification solutions (STEP 301), the cartridgetypically does not need any further hands-on monitoring by the operatorduring the useful life of the cartridge, even if re-calibration isrequired. However, if, during the initial verification (STEP 301), theconcentration of the analyte measured by one or more sensors isdetermined to be outside of the predetermined acceptable range for themeasured analyte concentration, calibration of the cartridge 37 usingone or more of the internal reference solutions is automaticallyinitiated (STEP 306). After the calibration of the sensors (STEP 306),the initial verification procedure performed in STEP 301 is repeated(STEP 308). The sensors are ready for sample measurement (STEP 302) ifall sensors measure the concentration of an analyte to have a valuewithin a predetermined acceptable range. If, during the repeated initialverification procedure (STEP 308), it is determined that the sensors arenot properly calibrated, the cartridge 37 is removed and a replacementcartridge 37 is introduced into the system (STEP 310). Althoughdescribed as being repeated twice, the determination of whether thesensors are properly calibrated may occur any number of times.

Further, the electrochemical sensor system 8 can record any or allinformation associated with one or more of the sensors, such as acalibration reading, at any time. In particular, the electrochemicalsensor system 8 can record this information in a storage element, suchas in memory (e.g., random access memory), a disk drive, a hard drive,or a database. Moreover, the electrochemical sensor system 8 may alsoflag particular stored information, such as if data is outside theacceptable range. This flag can designate data with an “error status” toindicate one or more values which are outside an acceptable range ofvalues.

Automatic Monitoring and Calibration

Referring still to FIG. 3A, the electrochemical sensor system 8 of thepresent invention can include an automatic sensor maintenance systemthat continuously and automatically monitors and calibrates each sensorwithin the system (STEP 304). The monitoring and calibration of eachsensor (STEP 304) occurs at regularly scheduled timed intervals duringwhich at least one of the internal reference solutions A, B, and C iscontinuously analyzed by the sensor(s) to verify the accuratecalibration of the sensor(s) in the system. The continuous monitoring ofeach sensor is interrupted only during a sample measurement due to thesample displacing the internal reference solution from the sensorchannel 56 or during a cleaning or calibration protocol. The use of atleast one of the internal reference solutions A, B, and C for monitoringthe calibration of each sensor eliminates the need for a periodicexternal calibration monitoring procedure (quality control) which usesan external verification solution.

Replacing an external monitoring procedure with an automatic monitoringprocedure using the internal reference solutions to check forcalibration of the sensor(s) eliminates the need for frequent hands-onmonitoring of the system by the operator using external verificationsolutions. The system of the present invention also uses the internalreference solutions A, B, and C on a continuous basis to calibrate eachsensor in the system when the monitoring procedure determines that oneor more sensor is uncalibrated. The calibration of the sensor occursautomatically according to the invention rather than manually. Followingthe calibration of each sensor, the system 8 automatically performs averification procedure to determine if each sensor is properlycalibrated. The verification procedure is performed using the internalreference solutions.

During STEP 304 of FIG. 3A, the sensor system 8 continuously monitorsfor failure patterns of one or more sensors. The sensor system 8periodically (e.g., every four hours) checks for A calibration. If thesensor system 8 detects a failure pattern with respect to internalreference solution A in STEP 312, then the sensor undergoes furtherfailure pattern analysis and corrective actions, described in moredetail in FIG. 4A. If the sensor system 8 does not detect a failurepattern with respect to internal reference solution A in STEP 312, theautomatic monitoring and calibration continues.

All sensors in the cartridge 37 are monitored continuously (STEP 304)with reference to the internal reference solution(s) within thecartridge. The sensor system 8 processes the sample (STEP 313). Thecontinuous analysis of the system includes the first measurement of theconcentration of at least one analyte in the internal reference solutionimmediately after processing sample (STEP 314). It is then determinedwhether the concentration of an analyte in the internal referencesolution measured by the sensor is outside the limits of thepredetermined acceptable range (i.e., in error) (STEP 316). If thedetermined concentration of the analyte in the internal referencesolution is not outside the predetermined acceptable range, then theautomatic monitoring and calibration continues (STEP 304) and thecartridge is ready for a sample. If, during the monitoring of theinternal reference solution (STEP 304), a determination of theconcentration of an analyte (first measurement) is detected by a sensorin a range outside a predetermined acceptable range (STEP 316), then thesystem determines whether a failure pattern is detected with respect tointernal reference solution B (STEP 317). If a failure pattern isdetected, the system 8 initiates another reading (second measurement) ofthe sensor with respect to the same internal reference solution (STEP318). If a failure pattern is not detected, the system 8 continues withits automatic monitoring and calibration (STEP 304).

Also referring to FIG. 3B, the sensor system 8 then compares theconcentration of the second measurement (from STEP 318) with theconcentration of the first measurement (from STEP 314) (STEP 320). Thesystem 8 then determines from this comparison if the drift error of thefirst measurement occurs in the same direction as the drift error of thesecond measurement (e.g., if both drift error values are positive orboth drift error values are negative) (STEP 321). Further, STEP 320 andSTEP 321 may together be referred to below as Block X.

If the drift error between the first measurement and the secondmeasurement are not both errors in the same direction (i.e., one drifterror is positive while the other drift error is negative) (STEP 321),then the sensor system 8 performs the operations in Block X with respectto the second measurement and the original measurement of the analyte inSTEP 322. If the drift error of the second measurement is in the samedirection as the drift error of the original measurement prior to thesample that caused the problem, then the system is ready to analyze asample (STEP 324).

If, in STEP 321, the drift error of the second measurement is in thesame direction (e.g., both positive or both negative) as the firstmeasurement, the sensor system 8 then calibrates the sensor withinternal reference solution A (STEP 326). The system 8 then determinesif a drift error pattern has been detected with respect to internalreference solution A (STEP 328). If no drift error pattern has beendetected, the system 8 returns to the automatic monitoring andcalibration (STEP 304).

If, however, the system 8 detects a drift error pattern with respect tointernal reference solution A (STEP 328), the system 8 initiates acleaning cycle of the sensor (STEP 330). Following the cleaning cycle ofthe sensor (STEP 330), the sensor system 8 again analyzes theconcentration (third measurement) of the analyte in the internalreference solution (STEP 332). The system 8 then executes the steps inBlock X with respect to the third measurement and the originalmeasurement prior to the sample that caused the problem (STEP 333). Ifboth drift errors are in the same direction, then the cartridge 37 isready for sample (STEP 324). If, however, the drift error of the thirdmeasurement is not in the same direction as the drift error of theoriginal measurement (STEP 333), then the sensor is unavailable forsample (STEP 334).

With continued reference to FIG. 3B, if the drift error of the secondmeasurement is not in the same direction as the drift error of the firstmeasurement (STEP 321) and the drift error of the second measurement isthe same direction as the drift error of the original measurement (STEP322), the sensor is ready for a sample measurement (STEP 324). If, onthe other hand, the drift error of the second measurement is determinednot to have the same direction as the drift error of the originalmeasurement (STEP 322), the sensor is again calibrated with internalreference solution A (STEP 326). Thus, in one embodiment, the comparisonof drift error directions for different measurements occurs three timesbefore stating that the cartridge 37 is unavailable to sample. In oneembodiment, the comparisons between the measurements of theconcentrations described above (and below) are performed by thecomparator 47 illustrated in FIG. 1.

Sensor Failure Pattern Analysis and Recognition

The present invention includes a method for determining failure patternsof the electrochemical sensor system. Included in the present inventionare systems and methods for detecting sensors which have becomeuncalibrated but have not been detected or corrected by the automaticmonitoring and calibration system. Such sensors exhibit failure patternsthat may be later used to identify these uncalibrated and undetectedsensors.

The method of determining failure patterns includes the steps ofexamining the performance of cartridges 37 that include at least oneuncalibrated sensor to identify characteristic failure patterns of thecartridge 37. The failed cartridges, which include at least oneuncalibrated sensor, are selected by testing the calibration of thesensors with external verification solutions. Thus, the selectedcartridges are cartridges which were determined by the above-describedinternal, automatic monitoring and calibration methods to be ready forsample measurement (STEP 324), but, as determined by an externalverification procedure, the sensors in these cartridges were notcalibrated properly. Determining the cause, failure pattern andcorresponding corrective action of the failed cartridges allows forimprovements to be made to the automatic monitoring and calibrationmethod of the system to prevent undetected failure of the same type. Thecorrective action(s) are performed by the corrective action device 49.

Failure patterns and corresponding corrective actions for thehematocrit, pO₂, pH, pCO₂, Na, K, and Ca sensors and with respect tointernal reference solutions A, B, and C are further described below.

Hematocrit

With respect to a hematocrit sensor, the sensor system 8 follows asimilar path to that of FIG. 3B. Also referring to FIG. 3C, the sensorsystem 8 first performs Block X between the second and firstmeasurements of the analyte in STEP 350. If the two drift errors of thetwo measurements are going in the same direction, the system 8 initiatesa cleaning cycle (STEP 352). The system 8 then initiates a thirdcalibration of the measurement (STEP 354) before performing theoperations in Block X with respect to the third measurement and theoriginal measurement (STEP 356). If the difference in drift errorbetween the third measurement and the original measurement is in thesame direction, the sensor system 8 determines if the sensor calibrationis within the range limits of the external verification solution (STEP358). If the sensor is within the range limits of the EVS (STEP 358),the sensor is ready for sample (STEP 360). If, however, the sensor isoutside of the acceptable range limits of the EVS (STEP 358), the sensoris not available for a sample (STEP 362).

If the sensor system 8 determines that the drift errors for the secondand first measurements are in different directions (STEP 350), then thesensor system performs the operations in Block X with respect to thesecond measurement and the original measurement (STEP 364). If the drifterror is in the same direction for both measurements, then the system 8initiates a fourth measurement of the calibration (STEP 366) and thenperforms the operations of Block X for the fourth measurement and thesecond measurement of the calibration (STEP 368). If the drift errorsare in the same direction, then the sensor system 8 performs thecorrective action by initiating a cleaning cycle (STEP 352), asdescribed above. If the drift errors are not in the same direction, thenthe system 8 performs the operations in Block X with respect to thefourth measurement and the original measurement. If the drift errors arein the same direction, then the cartridge is ready for sample (STEP360). If not, then the sensor is unavailable for sample (STEP 362).

Failure Patterns and Corrective Actions Related to Internal ReferenceSolution B

Failure patterns have been found to exist for the hematocrit, pO₂, pH,pCO₂, Na, K, and Ca sensors with respect to the internal referencesolution B. The failure patterns include a drift in the concentrationwith respect to the concentration of the internal reference solution B.The drift value is typically outside of pre-set limits with reference toan original measurement. The failure patterns occur after a samplemeasurement, and are typically caused by a blood clot on one or more ofthe sensors.

Referring to FIG. 4A, the electrochemical sensor system 8 firstdetermines if a failure pattern has been detected (STEP 400) withrespect to the internal reference solution B. This failure patterndetermination can include determining a failure pattern for one or moreof the hematocrit sensor, the pO₂ sensor, and/or one or more of the pH,pCO₂, Na, K, and Ca sensors.

The determination of a failure pattern for the pO₂ sensor (STEP 400)preferably includes determining a drift value with respect to theinternal reference solution B that is less than a pre-set lower limitwith reference to the original measurement. The lower limit for the pO₂sensor can be 12 mmHg less than the original measurement of the pO₂sensor. If no failure pattern with respect to internal referencesolution B is detected in STEP 400, then the automatic monitoring andcalibration continues (STEP 304) and the sensors are ready for a samplemeasurement.

The detection of failure patterns for the pH, pCO₂, Na, K, and/or Casensors (STEP 400) preferably includes detecting drift values withrespect to the internal reference solution B that are greater than apre-set upper limit or less than a pre-set lower limit with reference tothe original measurements. In one embodiment, the limits for the pHsensor are ±0.02. The limits for the pCO₂ sensor can be ±3 mmHg from theoriginal measurement. Similarly, the limits for the Na sensor can be ±3mM from the original measurement for a cartridge life greater than 5hours, and can be −2 mM to +8 mM for a cartridge life less than 5 hours.The limits for the K sensor may be ±0.3 mM from the originalmeasurement. The limits for the Ca sensor may be ±0.06 mM from theoriginal measurement.

In one embodiment, the detection of the failure patterns for the pH,pCO₂, Na, K, and Ca sensors (STEP 400) is confirmed by determiningwhether a reference shift of the internal reference solution B hadoccurred. In one embodiment, a reference shift is a shift in theconcentration of the internal reference solution (e.g., internalreference solution B).

If a reference shift is confirmed in the internal reference solution B,then the failure patterns for the pH, pCO₂, Na, K, and Ca sensors arenot valid and the sensor returns to automatic monitoring and calibration(STEP 304). If a reference shift is not confirmed in the internalreference solution B, then the failure patterns for the pH, pCO₂, Na, K,and Ca sensors are valid.

An occurrence of a reference shift of the reference electrode withrespect to internal reference solution B may be determined by numerousmethods. In one embodiment according to the invention, theelectrochemical sensor system 8 determines a reference shift bycalculating the difference in the potential difference (e.g., measuredin millivolts) between at least two consecutive measurements of theinternal reference solution B by the pH, Na, K, and Ca sensors. In someembodiments, the lowest value of a measurement by the four sensors issubtracted from the highest value of a measurement by the four sensors.The reference value is shifted if the resulting value is less than apredetermined reference value, preferably 0.6 millivolts.

The determination of a failure pattern for the hematocrit sensor (STEP400) preferably includes, for example, determining a drift value withrespect to the internal reference solution B that is greater than apre-set upper limit with reference to an original measurement. Theoriginal measurement, in all cases, refers to the calibrationmeasurement immediately prior to the calibration measurement thatexhibits a drift error. The upper limit of a drift value permissible foroperation of the hematocrit sensor is from, for example, 1%-10%,preferably 2%, greater than the original measurement of the hematocritsensor.

Once the failure patterns for the hematocrit, pO₂, pH, pCO₂, Na, K, andCa sensors with respect to the internal reference solution B have beendetected (STEP 400), a protocol of corrective actions is automaticallyinitiated (STEP 402-STEP 430). The protocol of corrective actions can beaccompanied by alerting the user of the sensor error by an alarm such aswarning lights on the device turning red and/or an error message beingdisplayed on the control screen.

Referring to FIG. 4A, for instance, if a failure pattern is detected forthe hematocrit sensor, the electrochemical sensor system 8 thendetermines if the failure pattern was only detected in the hematocritsensor (STEP 402). Referring also to FIG. 4B, if a failure pattern wasonly detected in the hematocrit sensor, the electrochemical sensorsystem 8 initiates a rinse protocol (STEP 406) of the sensor. The rinseprotocol (STEP 406), for example, includes changing the polarizationpotential of the glucose and lactate sensors from −0.26 V to −0.46 V,followed by a series of rinses of the sensors with internal referencesolution C. The rinse protocol (STEP 406) continues by performing apredetermined number of bubble flush loops (e.g., 10). A bubble flushloop includes the injection of an air bubble into the flow of therinsing solution as it flows along the sensors. The air bubbles in therinse provide a type of mechanical scrubbing of the sensors that theflow of rinse solution over the sensors does not provide. Thepredetermined number of bubble flush loops (e.g., 10) are followed by apredetermined number of rinses (e.g., 3) with internal referencesolution B. The rinse protocol (STEP 406) is completed by are-calibration of the sensors with respect to internal referencesolution B and by returning the polarization potential of the glucoseand lactate sensors from −0.46 V to −0.26 V.

In one embodiment, the rinse protocol is executed by a rinser. Therinser may be part of the corrective action device, the microprocessor,a separate component or part of any other component in theelectrochemical sensor system. The rinser may include a mechanicalrinsing mechanism which may be controlled, for instance, via a softwareprogram, a hydraulic system, a pneumatic system, and the like. In oneembodiment, the rinser includes the peristaltic pump 26 illustrated inFIG. 1.

Following the rinse protocol (STEP 406), the drift of the hematocritsensor with respect to the internal reference solution B is calculated(STEP 408) from the hematocrit measurement prior to the detection of thefailure pattern to the measurement after the rinse. If the drift of thehematocrit sensor is in error of greater than a predetermined threshold(e.g., ±2%) (STEP 410), then the hematocrit sensor fails and ispermanently disabled (STEP 412). If the hematocrit drift error is lessthan ±2%, then a failure pattern is not detected and the hematocritsensor is ready for use (STEP. 414). Following the hematocrit sensorbeing permanently disabled (STEP 412) or being determined ready for use(STEP 414), the corrective action protocol terminates and all sensorsother than the hematocrit sensor are ready for use (STEP 416).

Referring again to FIG. 4A, in the case in which failure patterns forthe pO₂, pH, pCO₂, Na, K, or Ca sensors are detected, the correctiveaction protocol initiates calibration with respect to the internalreference solution B of only the sensor(s) that exhibited a failurepattern (STEP 418). If a failure pattern is no longer detected followinga calibration with respect to the internal reference solution B, then acalibration with respect to the internal reference solution A isinitiated (STEP 420).

In one embodiment, if, after the calibration with internal referencesolution B (STEP 418), a failure pattern is still detected in any of thesensor(s) exhibiting a previous failure pattern, then a calibration withrespect to the internal reference solution B of only the sensor(s) thatexhibited a failure pattern is repeated a second time, and, ifnecessary, a predetermined number of times after the second time, suchas one additional time (for a total of three times).

If, after the third calibration (or any predetermined number ofcalibrations) with respect to the internal reference solution B (STEP418), a failure pattern is still detected in any of the sensor(s)exhibiting a failure pattern, then a calibration with respect to theinternal reference solution A is initiated (STEP 420).

The drift of the pO₂, pH, pCO₂, Na, K, and Ca sensors with respect tothe internal reference solution A is then determined for each sensorfrom the measurement immediately prior to the detection of the failurepattern and from the measurement immediately after the calibration ofthe sensor with respect to the internal reference solution A. If thedrift of the pO₂ sensor with respect to the internal reference solutionA is determined to be greater than the pre-set upper limit or issufficiently in error to be unrecordable in the storage element withreference to the original measurement (STEP 422), then corrective actioncontinues, beginning with a rinse of the sensors (STEP 424) as describedin FIG. 4C. Similarly, in one embodiment, if the drift of the pH, pCO₂,Na, K, or Ca sensors with respect to the internal reference solution Ais determined to be less than the pre-set lower limit with reference tothe original measurements (STEP 422), then the corrective actioncontinues with STEP 424 in FIG. 4C. Steps 518-522, as described above,are referred to below as the “Failure Pattern with Internal ReferenceSolution B Section.”

If the drift of the pH, pCO₂, Na, K, or Ca sensors with respect to theinternal reference solution A is determined to be within the pre-setlimits with reference to the original measurements (STEP 422), then thedrift error of the Na or Ca sensors with respect to internal referencesolutin B is considered (STEP 426) and the presence of a hematocritfailure pattern is considered (STEP 428). If the drift error of the Naor Ca sensors with respect to internal reference solution B is outsidethe pre-set limits with reference to the original measurements for thesensors (STEP 426) then the user is informed of an interference with thesensor(s) (STEP 430). Thiopental and benzalkonium are two compoundsthat, if present in the sample, will cause interference. Theelectrochemical sensor system accepts user acknowledgement of the drifterror of the Na or Ca sensors (STEP 424) in order for the sensors to beready for use and/or the automatic monitoring and calibration of thesensors to begin (STEP 304). If a hematocrit failure pattern is detected(STEP 428), then corrective action continues with the rinse of thesensors (STEP 430) (FIG. 4C). If a hematocrit failure pattern is notdetected (STEP 428) then the sensors are ready for use and the automaticmonitoring and calibration of the sensors begins (STEP 304). Moreover,steps 526-530 and the previous descriptions relating to these steps arereferred to below as “Drift Error Detected Section.”

Referring to FIG. 4C, the corrective action for sensors exhibiting adrift error or for when a hematocrit failure pattern is detectedcontinues by performing the rinse protocol (STEP 424), as previouslydescribed with respect to STEP 406. The sensor system 8 then executesthe Failure Pattern with Internal Reference Solution B Section (STEP432), as described in FIG. 4A. After executing the Failure Pattern withInternal Reference Solution B Section, the drift of the pO₂, pH, pCO₂,Na, K, and Ca sensors is determined for each sensor with respect to theinternal reference solution A, which was also described above withrespect to, for example, STEP 422. If a drift error is not detected,corrective action terminates and the sensors are ready for use (STEP434). If a drift error is detected, the sensor is permanently disabledfor the life of the cartridge (STEP 436). Moreover, the correctiveaction protocol is terminated and all non-disabled sensors are ready foruse (STEP 438).

Failure Patterns and Corrective Actions Related to Internal ReferenceSolution A

In addition to the failure patterns with respect to the internalreference solution B, failure patterns have been found to exist for thepO₂, pH, pCO₂, Na, K, and Ca sensors with respect to the internalreference solution A. Thus, the failure patterns include a drift errorwith respect to the internal reference solution A. The failure patternscan occur after a sample measurement in which the drift error istypically caused by a blood clot, and can occur after a calibration withrespect to the internal reference solution A.

Referring again to FIG. 4A, the references to the internal referencesolution B in the steps and description for FIG. 4A above are swappedwith references to the internal reference solution A when determiningfailure patterns and corrective actions related to internal referencesolution A.

For instance, the determination of a failure pattern for the pO₂ sensor(STEP 400) preferably includes determining a drift value with respect tothe internal reference solution A that is greater than a pre-set upperlimit with reference to the original measurements. The upper limit forthe pO₂ sensor can be, for example, 6 mmHg greater than the originalmeasurement. In one embodiment, the upper limit for the pO₂ sensor isbetween 4-10 mmHg. The failure patterns for the pH, pCO₂, Na, K, and Casensors include drift values with respect to the internal referencesolution A that are less than a pre-set lower limit with reference tothe original measurements. The lower limit for the pH sensor can be−0.03 from the original measurement. The lower limit for the pCO₂ sensorcan be −4 mmHg from the original measurement. The lower limit for the Nasensor can be −3 mM from the original measurement. The lower limit forthe K sensor can be −0.2 mM from the original measurement. The lowerlimit for the Ca sensor can be −0.12 mM from the original measurement.Alternatively, the limits of each sensor may vary with respect tointernal reference solution A or internal reference solution B.

Failure Pattern and Corrective Action Related to the pO₂ Sensor

A failure pattern specific to the pO₂ sensor has been found to exist.This failure pattern occurs infrequently and is not caused by thefouling of the sensor by a sample. The failure pattern for the pO₂sensor includes a drift value with respect to the internal referencesolution B that is a predetermined number of times (e.g., 1.5) greaterthan a pre-set upper limit with reference to the original measurement.The failure pattern also requires that the drift error does not occurduring the detection of a different type of failure pattern or duringthe corrective action initiated by a different type of failure pattern.

The corrective action of the failure pattern initiates a calibrationwith respect to internal reference solution A. Following thecalibration, if the drift of the pO₂ sensor is determined to be withinthe pre-set upper limits of drift with reference to the originalmeasurements then the corrective action is terminated and the sensor isready for use. If the drift of the pO₂ sensor is greater than a pre-setupper limit or is sufficiently in error to be unrecordable, then asecond calibration with respect to internal reference solution A isperformed. If the drift of the pO₂ sensor after the second calibrationis within the pre-set limits for drift with reference to the originalmeasurements, then the pO₂ sensor is permanently disabled. If, however,the drift of the pO₂ sensor after the second calibration is outside thepre-set limits for drift with reference to the original measurementsthen the corrective action is terminated and the pO₂ sensor is ready foruse.

Failure Pattern and Corrective Action Related to Detecting Air in theSensor

A failure pattern related to the detection of air in the sensor channelhas been found to exist. The failure pattern is caused by fouling of thesensor by a sample. The fouling causes a short circuit in the hematocritsensor and thus disabling the sensor's ability to detect whether liquidor air is contacting the sensor. The failure pattern includes twoconsecutive sensor errors that fail to detect air in the sensor channel.The failure pattern also requires that at least one sample was processedwithin 2 hours of the first sensor error failing to detect air.

The corrective action protocol initiates the rinse of the sensors.Following the rinse, if the sensor error failing to detect air iseliminated, then the corrective action is terminated and the sensor isready for use. If, following the rinse, the sensor error failing todetect air is not eliminated, then the user is notified that the sensorfunction could not be recovered and that the cartridge needs to bereplaced.

pCO₂ and pH Calibration Confirmation with Internal Reference Solution C

The following three checks have to be performed for pCO₂ in a cartridge37. Failing any of these checks constitutes pCO₂ failure and raising thepCO₂ flag.

1) Slope Check:pCO₂S=(XCO₂ MV+XPHMV)−(CCO₂ +CpHMV))/(pHMC−pHB) mV/decadepHS=(XpHMV−CpHMV)/(pHMCI−pHB) mV/decade

pCO₂S is the pH slope of the pCO₂ outer membrane. pHS is the slope ofthe pH outer membrane. XCO₂MV and XpHMV are the mV values from the last“X” readings for the pCO₂ and the pH sensors before the C. CCO₂MV andCpHMV are the mV values from the pCO₂ and the pH sensors from the Csolution, and pHMCI is the initial measured pH value for the C solution,as described in more detail below. pHB is the pH value for the Bsolution obtained from the cartridge bar-code. The “B” value shall beused in the above equation if no “X” value is available.

If pHS−pCO₂S≧pHSI−pCO₂SI+5, then the check fails and an internal flag israised for the pCO₂ sensor. In the above equation, “pHSI” and “pCO₂SI”are the initial pH slopes of the pH and pCO₂ outer membranes obtainedfrom the first cal C after warm-up, as described in more detail below.

2) Threshold Check:PCO2MC=PCO2B*10^((BPCO2MV−CPCO2MV)/S) mmHg

Where PCO2MC is the measured PCO2 value for the C solution, BCO2MV andCPCO2MV are the last B mV readings before the C and the C mV reading,respectively, S is the PCO2 slope from the last 2-point cal, and PCO2Bis the PCO2 value for the B solution obtained from the cartridgebar-code.

If PCO2MC−PCO2MCI is outside of the acceptable threshold range specifiedin section 11, then the PCO2 check fails. In the above equation PCO2MCIis the initial measured PCO2 in the C solution obtained from the firstCal C after warm-up.

3—Drift Check

If PCO2MC−PCO2MC′ (PCO2MC is obtain from Threshold Check above andPCO2MC′ is the previous PCO2MC) is outside of the acceptable drift rangespecified in section 11, then before reporting the drift failure anotherdrift check will be performed. In this alternate drift check, thePCO2MC′ is replaced with PCO2MC″ (PCO2MC″ is the measured PCO2 in the Csolution prior to PCO2MC′). If this alternate drift check passes, thenthe check will pass and the alternate check result will be reported. Ifthis alternate drift check fails, then the initial check (using PCO2MC′)will be reported. The alternate check is used only when threshold checkpasses.

pH Buffer Capacity Check During Calibration C

The following two checks have to be performed for pH in iQM cartridgesonly. Failing either of the two checks will constitute pH failure andraising the pH flag:

1—Threshold CheckpHMC=(BPHMV−CPHMV)/S+pHB mmol/L

pHMC is the measured pH value for the C solution, BPHMV is the last B mVreadings for the pH before the C, CPHMV is the C mV values from the pHchannel, S is the pH slope from the last 2-point cal, and pHB is the pHvalue for the B solution obtained from the cartridge bar-code.

If PHMC−PHMCI is outside of the acceptable threshold range specified insection 11, then the check fails and an internal flag has to be raisedfor the pH sensor. In the above equation PHMCI is the initial measuredpH in the C solution obtained from the first Cal C after warm-up.

2—Drift Check

If PHMC−PHMC′ (PHMC is obtained from Threshold Check above and PHMC′ isthe previous measured pH in the C solution) is outside of the acceptabledrift range specified in section 11, then before reporting the driftfailure another drift check will be performed. In this alternate driftcheck, the PHMC′ is replaced with PHMC″ (PHMC″ is the measured pH in theC solution prior to PHMC′). If this alternate drift check passes, thenthe check will pass and the alternate check result will be reported. Ifthis alternate drift check fails, then the initial check (using PHMC′)will be reported. The alternate check is used only when threshold checkpasses.

The pH and PCO2 values of the C solution are established during thefirst Cal C after warm-up. Therefore, the pH/PCO2 checks actually startswith the second Cal C after cartridge warm-up. However, if the pH orPCO2 slope immediately before the first Cal C after warm-up isincalculable, then pH/PCO2 checks will not start until the next Cal C.This logic will apply to subsequent Cal C's until the initial measuredvalues for pH and PCO2 outer membranes are established.

The pH and PCO2 values for the C solution are established from thefollowing equations:pHMCI=(BPHIMV−CPHIMV)/pH slope+pHB pH unitPCO2MCI=PCO2B*10^((BPCO2IMV−CPCO2IMV)/PCO2 slope) mmHgwhere BPHIMV and CPHIMV are the pH mV outputs from the B before the Cand the first C after warm-up, BPCO2IMV and CPCO2IMV are the PCO2 mVoutputs from the B before the C and the first C after warm-up, pH slopeand PCO2 slope are the current pH and PCO2 slope values prior to thefirst C, and pHB and PCO2B are the pH and PCO2 values for the B obtainedfrom the cartridge bar-code.

The initial pH and PCO2 outer membrane slopes are obtained from thefirst Cal C after cartridge warm-up. These values are calculated formthe following equations:PHSI=(XPHIMV−CPHIMV)/(pHMCI−pHB) mV/decadePCO2SI=((XPCO2IMV+XPHIMV)−(CPCO2IMV+CPHIMV))/(pHMCI−pHB) mV/decade

PHSI and PCO2SI are the initial pH slopes of the pH and PCO2 outermembranes, XPHIMV and XPCO2IMV are the mV values form the last “X”readings for the pH and PCO2 sensors before the first C, and CPHIMV andCPCO2IMV are the mV values from the pH and PCO2 sensors from the first Cafter warm-up. The “B” value shall be used in the above equations if no“X” value is available.

In one embodiment, the sensor system 8 may maintain and display acorrective action log. Referring to FIG. 5, in one embodiment the sensorsystem 8 provides a corrective action report 500 regarding theperformance and corrective action(s) taken. The corrective action report500 provides a list of corrective actions taken, such as if the sensoroutput was adjusted, if the fluidics were checked, and/or if a testneeded to be repeated.

In particular embodiments and referring to FIG. 6, the sensor system 8may maintain and display a delta chart. These can help determine theaccuracy of the sensors and or internal reference solutions. The sensorsystem 8 may also enable the verification and checking of the electroniccomponents in the system 8, such as verifying the operation of themicroprocessor 40 through, for instance, one or more tests. Thus, thesensor system 8 can display, for example, an error log and a delta chartshowing drift errors. Further, if the sensor system 8 encounters anerror, the system 8 displays an error message. In some embodiments, theerror message stays displayed until the user clears the message. In yetother embodiments, the sensor system 8 sounds an alarm when an erroroccurs.

In other embodiments, the sensor system 8 is a blood glucose monitoringdevice. The blood glucose device measures a user's blood glucose levelfrom a blood sample applied to a conventional blood testing strip.Although users of a typical blood glucose monitors have tocalibrate/check the meter's accuracy by applying an external controlsolution onto the blood testing strip, the sensor system 8 calibratesand checks the system automatically and internally, without userintervention. An example of a conventional blood glucose monitorincludes, but is not limited to, the ONETOUCH devices from LifeScan,Inc.

In other embodiments, the sensor system 8 measures blood urea nitrogen(BUN), which is a metabolic by-product (in the liver) from the breakdownof blood, muscle, and protein. Blood urea nitrogen can be measured froma venipuncture specimen. The sensor system 8 would perform thesemeasurements while not requiring external calibration. In yet anotherembodiment, the sensor system 8 measures cholesterol, creatine, and thelike in the same fashion.

Although the present invention has been described with reference tospecific details, it is not intended that such details should beregarded as limitations upon the scope of the invention, except as andto the extent that they are included in the accompanying claims.

What is claimed is:
 1. A method for monitoring sensor system performancefor in vitro diagnostic testing of patient samples, comprising: (a)providing a plurality of sensors and one or more internal referencesolutions in a replaceable cartridge for use in a sensor system, saidinternal reference solutions comprising a plurality of analytes eachhaving a known concentration; (b) determining a first response of onesensor of the plurality of sensors to one of the plurality of analytesin a first internal reference solution in between testing of patientsamples; (c) determining a second response of the one sensor of theplurality of sensors to the one of the plurality of analytes in thefirst internal reference solution; (d) taking action in response to thedetermining in steps (b) and (c) to provide continued testing of patientsamples by initiating a cleaning cycle if the first response to theanalyte in step (b) is substantially similar to the second response tothe analyte in step (c) and the first and the second responses aresubstantially dissimilar to the response of the sensor to the knownconcentration of the analyte; (e) optionally signaling for replacementof said cartridge when the action of step (d) fails to provide continuedtesting of patient samples.
 2. The method of claim 1 wherein the actionfurther comprises calibration of the one sensor of the plurality ofsensors using the first or another internal reference solution.
 3. Themethod of claim 1 wherein at least one of the plurality of sensorscomprises an electrochemical sensor.
 4. The method of claim 1 whereinthe action of step (d) further comprises a corrective action comprisingproviding a rinsing solution before step (e) if the action in step (d)fails to provide continued patient testing.
 5. The method of claim 1wherein the action of step (d) responds to an error in at least one ofslope and drift.
 6. The method of claim 1 wherein the action of step (d)responds to at least one of a blood clot and an interference.
 7. Amethod for monitoring performance of a sensor for analyzing patientfluid samples during the use life of the sensor, the method comprising:(i) containing the sensor and a first and another internal referencesolutions in a replaceable cartridge; (ii) verifying the sensorperformance during the use life of the sensor in between analysis ofpatient fluid samples using the first internal reference solution toevaluate the sensor performance; (iii) automatically verifying thesensor performance using said first or another internal referencesolution in the event of a failure to verify in step (ii), comprising(a) determining a first measurement by the sensor of a knownconcentration of an analyte in said first or another internal referencesolution, (b) determining a second measurement by the sensor of theknown concentration of the analyte in said reference solution in which ameasurement was determined in step (a), (c) taking action based on thedetermined measurements of steps (a) and (b), to provide continuedtesting on patient fluid samples, and (d) signaling for replacement ofsaid cartridge when taking action in step (c) fails to provide continuedtesting on patient fluid samples; (iv) verifying the sensor performancebefore analyzing a patient fluid sample and thereafter verifying thesensor performance according to steps (ii) and (iii); and, (v) acceptingthe sensor for analysis of patient fluid samples if the secondmeasurement is dissimilar to the first measurement and the secondmeasurement is substantially similar to the known concentration of theanalyte.
 8. The method according to claim 7 wherein the action of step(c) comprises recalibrating the sensor with an internal referencesolution if the sensor performance in step (iii) is outside a presetrange of acceptable sensor performance.
 9. The method according to claim7 wherein the action of step (c) comprises recalibrating the sensor withthe first internal reference solution if the first measurement and thesecond measurement are substantially dissimilar and the firstmeasurement is substantially similar to the known concentration of theanalyte.
 10. The method according to claim 7 wherein the action of step(c) comprises recalibrating the sensor with the first or anotherinternal reference solution if the first measurement is substantiallydissimilar to the second measurement and the first and the secondmeasurements are substantially dissimilar to the known concentration ofthe analyte.
 11. The method according to claim 7 wherein the sensor isan electrochemical sensor.
 12. The method according to claim 7 whereinthe sensor performance comprises accuracy of the sensor measurement. 13.The method of claim 1 wherein step (b) occurs immediately before eachpatient sample.
 14. The method of claim 1, further comprising providinga rinsing solution in the replaceable cartridge.